Tin polyoxaalkanecarboxylates and compositions containing them

ABSTRACT

Tin polyaalkanecarboxylates having the formula [(R 1   p R 2   q Sn) r O s ] t  wherein R 1  represents C 1 -C 6  alkyl, branched or straight, substituted or not by one or more hydroxyl groups or halogen atoms, or a phenyl group, substituted or not by one or more hydroxyl groups or halogen atoms, R 2  is carboxylic residue selected from (I), (II), (III) or (IV); and p, q, r, s and t have the following meanings: P=3, q=1, r=1, s=) and t=1, p=2, q=2, r=1, s=0, and t=1, p=2, q=1, r=2, s=1 and t=2, have anti-tumor activity.

[0001] The invention relates to novel tin polyoxaalkanecarboxylates and to anti-tumour compositions containing such compounds.

[0002] The anti-tumour activity of tin compounds is known; it is also known that the anti-tumour activity of tin compounds could be enhanced by increasing their solubility in water.

[0003] The invention now provides water-soluble tin compounds which show strong in vitro anti-tumour activities against a broad spectrum of tumours, as appears from the experimental part, disclosed hereinafter.

[0004] More specifically the invention relates to tin polyoxaalkanecarboxylates having the formula

[(R ¹ _(p) R ² _(q) S _(n))_(r) O _(s)]_(t)

[0005] wherein

[0006] R¹ represents C₁-C₆ alkyl, branched or straight, substituted or not by one or more hydroxyl groups or halogen atoms, or a phenyl group, substituted or not by one or more hydroxyl groups or halogen atoms,

[0007] R² is a carboxylic residue selected from:

[0008] and p, q, r, s and t have the following meanings:

[0009] p=3, q=1, r=1, s=0 and t=1;

[0010] p=2, q=2, r=1, s=0 and t=1;

[0011] p=2, q=1, r=2, s=1 and t=2.

[0012] According to a preferred embodiment of the invention, represents R¹ a phenyl group or a n-butyl group in a compound having formula (1), (2) or (3).

[0013] The compounds according to the invention can be synthesized by effecting a condensation reaction between a carboxylic acid having formula

[0014] with triaryltin hydroxide, trialkyltin acetate or dialkyltin oxide, preferably triphenyltin hydroxide, tri-n-butyltin acetate or di-n-butyltin oxide, according to the following reaction schemes:

[0015] a) RCOOH+(C₆H₅)₃SnOH→(C₆H₅)₃SnOCOR+H₂O

[0016] b) RCOOH+Bu₃SnOCOCH₃→Bu₂SnOCOR+CH₃COOH

[0017] c) 2RCOOH+Bu₂SnO→Bu₂Sn(OCOR)₂+H₂O

[0018] d) 2RCOOH+2Bu₂SnO→½{[Bu₂(RCOO)Sn]₂O}₂+H₂O

[0019] Different media and methods can be used to synthesize such derivatives

[0020] 1) the condensation can be performed in toluene/ethanol. The water formed during the condensation is eliminated by azeotropic distillation (Dean-Stark funnel)

[0021] 2) benzene can be used instead of toluene/ethanol

[0022] 3) these compounds can also be prepared by a two-step procedure, dibutyltin oxide being first condensed with n-propanol to yield tetrabutyldipropoxydistannoxane:

2Bu₂SnO+2PrOH→(PrOSnBu₂)₂O+H₂O

[0023] An a second step, the carboxylic acid is added at room temperature to this tetrabutyldipropoxydistannoxane in the desired molar ratio.

[0024] The compounds synthesized by one of these methods were characterized by elemental analysis, ¹H, ¹³C and ¹¹⁷Sn NMR, electrospray mass spectrometry and ^(119m)Sn Mössbauer spectroscopy. Chromatography on Sephadex LH-20 proved to be a very efficient method to separate 3 (or 7) from 4 (or 8), or 11, 12, 15 and 16 from the starting carboxylic acid.

[0025] The structures of the compounds synthesized are depicted below

GENERALITIES AND ABBREVIATIONS

[0026] NMR spectra: CDCl₃ solutions; ¹H and ¹³C chemical shifts δ in ppm vs. TMS, homonuclear coupling constants in Hz, in parentheses; Mössbauer parameters (quadrupole splitting QS, isomers shift IS, and band widths Γ₁ and Γ₂) in mm/s; s: singlet; d: doublet; dd: doublet of doublets; m: complex pattern; t: triplet; tq: triplet of quartets; ψs, pseudo-singlet.

[0027] Electrospray mass spectra: positive monoisotopic ions (¹²C, ¹H, ¹⁶O, ²³Na, ³⁹K, ¹²⁰Sn). Na and/or K are already present in the electrospray mass spectra of the starting carboxylic acids.

[0028] Charaterization of Compounds 1 to 15

[0029] Compound 1: triphenyltin 4,7,10,13,16,19-hexaoxadicyclo[16.4.0]dicosa-1,3 (20 ,21-triene-1-carboxylate prepared according to method 1,

[0030] 10 h of reflux, recrystallized from diethyl ether/hexane, m.p. 110-1 12° C., yield 98%, elemental analysis: exp. (calc. for C₃₅H₃₈SnO₈): C: 60.2 (59.60); H: 5.5 (5.43); ¹H NMR: 7.7-7.8, m, H(o) & H(5); 7.62, d (⁴J(¹H-¹H)=2), H(3); 7.4-7.5, m, H(m) & H(p); 6.91, d (³J(¹H-¹H)=9), H(6); 4.1-4.3, m, H(8) & H(17); 3.8-4.0, m, H(9) & H(16); 3.6-3.8, m, H(10), H(11), H(14) & H(15); 3.67, ψs, H(12) & H(13); ¹³C NMR: 172.7, C(7); 152.9, C(1); 148.0, C(2); 138.5, C(i); 137.0, C(o) ²J(^(117/119)Sn—¹³C)=47/49; 130.2, C(p) ⁴J(^(117/119)Sn—¹³C)=13; 129.0, C(m) ³J(^(117/119)Sn—¹³C)=61/63; 125.1, C(5); 122.8, C(4); 114.9, C(3); 111.7, C(6); 70.80 & 70.77, C(10) & C(15); 70.71 & 70.66, C(12) & C(13); 70.53, 70.51, 69.4, 69.2, 68.8 & 68.6, C(8), C(9), C(11), C(14), C(16) & C(17); ¹¹⁷Sn NMR: −115.7; electrospray MS: M+K+⁺(m/z=745), 14%; M+Na⁺, 100%; Mössbauer: QS: 2.26; IS: 0.55; Γ₁: 1.34; Γ₂: 1.32.

[0031] Compound 2: tri-n-butyltin 4,7,10,13,16,19-hexaoxadicyclo[16.4.0]dicosa-1,3(20) ,21-triene-1-carboxylate prepared according to method 1,

[0032] 4 h of reflux, recryst. hexane/chloroform, m.p. 45-47° C., yield 80%, elemental analysis: exp. (calc. for C₂₉H₅₀SnO₈.H₂O): C: 52.5 (52.50); H: 8.3 (7.90); ¹H NMR: 7.63, dd (³J(¹H-¹H)=8; ⁴J(¹H-¹H)=2), H(5); 7.54, d (⁴J(¹H-¹H)=2), H(3); 6.82, d (³J(¹-¹H)=8), H(6); 4.1-4.3, m, H(8) & H(17); 3.8-4.0, m, H(9) & H(16); 3.6-3.8, m, H(10), H(11), H(14) & H(15); 3.65, ψs, H(12) & H(13);=2, HOH; 1.6-1.7, m H(β); 1.2-1.3, m, H(α) & H(γ); 0.89, t (³J(¹-¹H)=7), H(δ); ¹³C NMR: 171.4, C(7); 152.2, C(1); 148.1, C(2); 125.0, C(4); 124.2, C(5); 115.0, C(3); 112.1, C(6); 70.96 & 70.84, C(10) & C(15); 70.77 & 70.73, C(12) & C(13); 70.66, 70.61, 69.5, 69.4, 68.9 & 68.8, C(8), C(9), C(11), C(14), C(16) & C(17); 27.9, C(β) ²J(^(117/119)Sn—¹³C)=20; 27.0, C(γ) ³J(^(117/119)Sn—¹³C)=62/65; 16.6, C(α) ¹J(^(117/119)Sn—¹³C)=341/358; 13.7, C(δ); ¹¹⁷Sn NMR: 108.2; electrospray MS: M+Na⁺ (m/z=669), 6%; M+H₂O+H⁺, 9%; M+H⁺, 11%; Mössbauer: QS: 3.40; IS: 1.39; Γ₁: 0.72; Γ₂: 0.85.

[0033] Compound 3: di-n-butyltin bis[4,7,10,13,16,19-hexaoxadicyclo[16.4.0]dicosa-1,3(20),21-triene-1-carboxylate, prepared according to method 1,

[0034] 6 h of reflux, recryst. hexane/chloroform, m.p. 125-127° C., yield 96%, elemental analysis: exp. (calc. for C₄₂H₆₄SnO₁₆): C: 53.5 (53.46); H: 7.1 (6.84); ¹H NMR: 7.73, d (³J(¹-¹H)=8) , H(5); 7.58, s, H(3); 6.86, d (³J(¹-¹H)=8), H(6); 4.1-4.3, m, H(8) & H(17); 3.8-4.0, m, H(9) & H(16); 3.6-3.8, m, H(l0), H(11), H(14) & H(15); 3.65, ψs, H(12) & H(13); 1.7-1.8, m, H(β) & H(α); 1.37, tq, (³J(¹-¹H)=7, ³J(¹-¹H)=7), H(γ); 0.86, t (³J(¹-¹H)=7), H(δ); ¹³C NMR: 175.7, C(7); 153.3, C(1); 148.3, C(2); 124.9, C(5); 122.7, C(4); 115.3, C(3); 112.3, C(6); 70.9, C(10) & C(15); 70.81 & 70.76, C(12) & C(13); 70.73 & 70.67, 69.5, 69.4, 69.2 & 69.0, C(8), C(9), C(11), C(14), C(16) & C(17); 26.7, C(β) ²J(^(117/119)Sn-¹³C)=33; 26.3, C(γ) ³J(^(117/119)Sn-¹³C)=95; 25.4, C(α) ¹J(^(117/119)Sn—¹³C)=569/596; 13.5, C(δ); ¹¹⁷Sn NMR: −156.2; electrospray MS: M+Na⁺ (m/z 967), 100%; Mössbauer: QS: 3.41; IS: 1.44; ψ₁: 10.94; ψ₂: 0.94.

[0035] Compound 4: bis{di-n-butyl-[4,7,10,13,16,19-hexaoxadicyclo[16.4.0]dicosa-1,3(20),21-triene-1-carboxylato]tin}oxide, prepared according to method 3

[0036] 12 h of reflux, Sephadex LH-20, elution with chloroform/methylene chloride; recryst. hexane/chloroform, m.p. 96-98° C., yield 90%, elemental analysis: exp. (calc. for C₁₀₀H[₆₄Sn₄O₃₄): C: 50.0 (50.35); H: 7.1 (6.94); ¹H NMR: 7.54, d (³J(¹H-¹H)=8), H(5); 7.49, s, H(3); 6.84, d (³J(¹-¹H)=8), H(6); 4.1-4.3, m, H(8) & H(17); 3.8-4.0, m, H(9) & H(16); 3.6-3.8, m, H(10), H(11), H(14) & H(15); 3.62, ψs, H(12) & H(13); 1.6-1.8, m, H(β); 1.4-1.6, m, H(α); 1.1-1.4, m, H(γ); 0.7-0.9, m, H(8); ¹³C NMR: 172.6, C(7); 152.5, C(1); 148.3, C(2); 126.3, C(4); 124.0, C(5); 115.3, C(3); 112.4, C(6); 70.8, C(10) & C(15); 70.7 & 70.6, C(12) & C(13); 70.6, 70.5, 69.42, 69.35, 69.1 & 68.9, C(8), C(9), C(11), C(14), C(16) & C(17); 26.7 & 26.6, C(β); 27.6 & 27.4, C(γ); 29.5 & 28.3, C(α); 13.5 & 13.4, C(δ); ¹¹⁷Sn NMR: −213.0 & −217.3; electrospray MS: M/2+K⁺ (m/z=1233), 11%:; Mössbauer: QS: 3.36; IS: 1.27; Γ₁: 0.96; Γ₂: 0.99.

[0037] Compound 5: triphenyltin 4,7,10,13,16-pentaoxadicyclo[13.4.0]cosa-1,3 (17),18-triene-1-carboxylate, prepared according to method 2,

[0038] 48 h of reflux, recryst. hexane, m.p.: 130-131° C., yield 95%, elemental analysis: exp. (calc. for C₃₃H₃₄SnO₇.1 H₂O): C: 58.4 (58.34); H: 5.7 (5.35); ¹H NMR: 7.7-7.8, m, H(o) & H(5); 7.60, d (⁴J(¹H-¹H)=2), H(3); 7.4-7.5, m, H(m) & H(p); 6.82, d (³J(¹H-¹H)=8), H(6); 4.1-4.2, m, H(8) & H(15); 3.8-3.9, m, H(9) & H(14); 3.73, ψs, H(10), H(11), H(12) & H(13);=2, HOH; ¹³C NMR: 172.8, C(7); 153.1, C(1); 148.3, C(2); 138.7, C(i); 136.9, C(o) ²J(^(117/119)Sn—¹³C)=47/49; 130.1, C(p) ⁴J(^(117/119)Sn—¹³C)=13; 128.9, C(m) ³J(^(117/119)Sn—¹³C)=62/65; 125.2, C(5); 123.3, C(4); 115.7, C(3); 112.1, C(6); 70.95 & 70.92, C(8) & C(15); 70.31 & 70.23, C(9) & C(14); 69.3, 69.2, 69.9 & 68.5, C(10), C(11), C(12) & C(13); ¹¹⁷Sn NMR: −116.3; electrospray MS: M+K⁺ (m/z=701, 67%); M+Na⁺, 73%; Mössbauer: QS: 2.77; IS: 1.23; Γ₁: 0.94; Γ₂: 0.88.

[0039] Compound 6: tri-n-butyltin 4,7,10,13,16-pentaoxadicyclo 13.4.0]cosa-1,3 (17),18-triene-1-carboxylate, 20 prepared according to method 2,

[0040] 25 h of reflux, Sephadex LH-20, elution with chloroform/methylene chloride, liquid; yield 90%; elemental analysis: exp. (calc. for C₂₇H₄₆SnO₇.½ H₂O): C: 53.1 (53.14); H: 7.8 (7.77); ¹H NMR: 7.63, dd (³J(¹-¹H)=8; ⁴J(¹-¹H)=2), H(5); 7.54, d (⁴J(¹H-¹H)=2), H(3); 6.82, d (³J(¹-¹H)=8), H(6); 4.1-4.2, m, H(8) & H(15); 3.8-3.9, m, H(9) & H(14); 3.73, ψs, H(10), H(11), H(12) & H(13); 1.6-1.7, m, H(β); 1.2-1.4, m, H(α) & H(γ); 0.89, t (³J(¹H-¹H)=7), H(δ); ¹³C NMR: 171.4, C(7); 152.5, C(1); 148.4, C(2); 125.1, C(4); 124.4, C(5); 115.5, C(3); 112.3, C(6); 71.2, C(8) & C(15); 70.57 & 70.52, C(9) &° C(14); 69.6, 69.5, 69.1 & 68.9, C(10), C(11), C(12) & C(13); 27.9, C(β) ²J(^(117/119)Sn—¹³C)=20; 27.0, C(γ) ³J(^(117/119)Sn—¹³C)=62/65; 16.6, C(α) ¹J(^(117/119)Sn—¹³C)=350/362; 13.6, C(δ); ¹¹⁷Sn NMR: 107.4; electrospray MS: M+Na+(m/z=625), 5%; M+NH₄ ⁺, 9%; Mössbauer: QS: 3.29; IS: 1.45; Γ₁: 0.94; Γ₂: 0.88.

[0041] Compound 7: di-n-butyltin bis[4,7,10,13,16-pentaoxadicyclo[13.4.0]cosa-1,3(17),18-triene-1-carboxylate], prepared according to methode 2,

[0042] 48 h of reflux, recrystallized from petroleum ether/methylene chloride, m.p.: 130-1329C; yield 98%; elemental analysis: exp. (calc. for C₃₈H₅₆SnO₁₄): C: 53.9 (53.35); H: 6.7 (6.60); ¹H NMR: 7.74, dd (³J(¹-¹H)=8, ⁴J(¹-¹H)=2), H(5); 7.59, d (⁴J(¹H -¹H)=2) , H(3); 6.86, d (³J(¹H- ¹H)=8), H(6); 4.1-4.2, m, H(8) & H(15); 3.8-4.0, m, H(9) & H(14); 3.75, ψs, H(10), H(11), H(12) & H(13); 1.7-1.8, m, H(β) & H(α); 1.38, tq (³J(¹H-¹H)=7, ³J(¹H-¹H)=7), H(γ); 0.86, t (³J(¹H-¹H)=7), H(8); ¹³C NMR: 175.8, C(7); 153.5, C(l); 148.5, C(2); 125.0, C(5); 122.9, C(4); 115.4, C(3); 112.2, C(6); 71.11 & 71.09, C(8) & C(15); 70.39 & 70.31, C(9) & C(14); 69.4, 69.2, 69.0 & 68.6, C(10), C(11), C(12) & C(13); 26.7, C(β), ²J(117/119Sn—¹³C)=34; 26.4, C(γ), ³J(^(117/119)Sn—¹³C)=103; 25.5, C(α), ¹J(^(117/119)Sn—¹³C)=561/588; 13.6, C(δ); ¹¹⁷Sn NMR: −156.8; electrospray MS: M+Na⁺ (m/z=879), 27%, M+K⁺, 27%; Mössbauer: QS: 3.28; IS: 1.41; Γ₁: 0.92; Γ₂: 0.93.

[0043] Compound 8: triphenyltin 3,6-diheptanoate, prepared according to method 2,

[0044] 8 h of reflux, recrystallized from hexane/chloroform, m.p.: 100-102° C., yield 95%, elemental analysis: exp. (calc. for C₁₃H₂₄SnO₄): C: 57.4 (57.18); H: 4.7 (5.01); ¹H NMR: 7.7-7.8, m. H(o); 7.4-7.5, m, H(m) & H(p); 4.25, s, H(2); 3.7-3.8, m, H(4); 3.5-3.6, m, H(5); 3.35, s, H(7); 13C NMR: 176.5, C(1); 137.7, C(i); 136.8, C(o) ²J(^(117/119)Sn—¹³C)=49; 130.2, C(p) ⁴J(^(117/119)Sn—¹³C)=13; 128.9, C(m) ³J(^(117/119)Sn—¹³C)=62/65; 72.0, C(5); 70.6, C(4); 69.0, C(2); 59.0, C(7); ¹¹⁷Sn NMR: −100.0; electrospray MS: M+Na⁺ (m/z=507), 5%, M+H⁺, 2%; Mössbauer: QS: 3.60; IS: 1.24; Γ₁: 0.85; Γ₂: 0.79.

[0045] Compound 9: tri-n-butyltin 3,6-diheptanoate, prepared according to methode 2,

[0046] 8 h of reflux, Sephadex LH-20, elution with methylene chloride, liquid, yield 95% elemental analysis: exp. (calc. for C₁₇H₃₆SnO₄.½ H2O): C: 47.4 (47.27); H: 8.6 (8.63);; ¹H NMR: 4.09, S, H(2); 3.6-3.7, m, H(4); 3.5-3.6, m, H(S); 3.36, S. H(7);=2, HOH; 1.5-1.6, m, H(β); 1.2-1.4, m, H(α) & H(γ); 0.88, t (3J(¹-¹H)=7), H(δ); 3C NMR: 175.2, C(l); 71.9, C(S); 70.4, C(4); 69.0, C(2); 59.0, C(7); 27.8, C(β) ²J(^(117/119)Sn—¹³C)=20; 27.1, C(γ) ³J(^(117/119)Sn—¹³C)=64/67; 16.6, C(α) ¹J(^(117/119)Sn—¹³C)=338/355; 13.7, C(8); ¹¹⁷Sn NMR: 120.7; electrospray MS: M+Na⁺ (m/z=447), 7%; Mössbauer: QS: 3.81; IS: 1.47; Γ₁: 1.15; Γ₂: 1.14.

[0047] Compound 10: di-n-butyltin bis(3,6-diheptanoate), prepared according to method 3,

[0048] 12 h of reflux, liquid, yield 98%; elemental analysis: exp. (calc. for C₁₈H₃₆SnO₈): C: 43.4 (43.31); H: 7.5 (7.27); ¹H NMR: 4.16, s, H(2); 3.6-3.8, m, H(4); 3.5-3.6, m, H(5); 3.36, s, H(7); 1.6-1.7, m, H(β) & H(α); 1.34, tq (³J(¹-¹H)=7, ³J(¹-¹H)=7), H(γ); 0.87, t (³J(¹H-¹H)=7), H(δ); ¹³C NMR: 178.3, C(1); 71.8, C(5); 70.7, C(4); 68.6, C(2); 59.0, C(7); 26.5, C(β) ²J(^(117/119)Sn—¹³C) 34; 26.3, C(γ) ³J(^(117/119)Sn—¹³C)=98/102; 25.7, C(α) ¹J(^(117/119)Sn—¹³C)=538/567; 13.4, C(δ); ¹¹⁷Sn NMR: −124.7; electrospray MS: M+Na⁺ (m/z=523), 77%; M+K⁺, 13%; Mössbauer: QS: 3.90; IS: 1.44; Γ₁: 1.28; Γ₂: 1.02.

[0049] Compound 11: bis[di-n-butyl(3,6-dioxaheptanoato)tin]oxide, prepared according to method 3,

[0050] 12 h of reflux, Sephadex LH-20, elution with methylene chloride, liquid, yield 80%; elemental analysis: exp. (calc. for C₅₂H₁₀₈Sn₄O₁₈.2H₂O): C: 40.7 (40.76); H: 7.2 (7.37); ¹H NMR: 3.95, s, H(2); 3.6-3.7, m, H(4); 3.5-3.6, m, H(5); 3.34, s, H(7);˜2, HOH; 1.5-1.7, m, H(β); 1.3-1.5, m, H(α); 1.30, tq, (³J(¹H-¹H)=7, ³J(¹H-¹H)=7), H(γ); 0.86, m, H(δ); ¹³C NMR: 174.9, C(1); 71.8, C(5); 70.2, C(4); 69.8, C(2); 58.9, C(7); 27.5 & 27.2, C(β); 26.8 & 26.7, C(γ); 29.0 & 26.3, C(α); 13.57 & 13.55, C(δ); ¹¹⁷Sn NMR: −204.8 & −215.8; electrospray MS: M/2+Bu₂SnOH⁺(m/z=1001), 40%; Mössbauer: QS: 3.42; IS: 1.34; Γ₁: 1.22; Γ₂: 1.18.

[0051] Compound 12: triphenyltin 3,6,9-trioxadecanoate, prepared according to method 2,

[0052] 8 h of reflux, recryst. diethyl ether/methylene chloride, m.p.: 109-111° C., yield 92%, elemental analysis: exp. (calc. for C₂₅H₂₈SnO₅ ): C: 57.1 (56.96); H: 5.4 (5.36);; ¹H NMR: 7.7-7.8, m, H(o); 7.4-7.5, m, H(m) & H(p); 4.22, s, H(2); 3.7-3.8, m, H(4); 3.6-3.7, m, H(5); 3.5-3.6, m, H(7); 3.4-3.5, m, H(8); 3.34, s, H(10); ¹³C NMR: 176.4, C(1); 137.8 C(i); 136.9, C(o) ²J(^(117/119)Sn—¹³C)=47-50; 130.2, C(p) ⁴J(^(117/119)Sn—¹³C)=13; 128.9, C(m) ³J(^(117/119)Sn—¹³C)=63/66; 72.0, C(8); 70.7, 70.7 & 70.5, C(4), C(5) & C(7); 69.0, C(2); 59.0 C(10);¹¹⁷Sn NMR: −103.2; electrospray MS: M+K⁺(m/z=567), 2%; M+Na⁺, 11%; M+H⁺, 6%; Mössbauer: QS: 3.44; IS: 1.29; Γ₁: 0.91; Γ₂: 0.87.

[0053] Compound 13: tri-n-butyltin 3,6,9-trioxadecanoate, prepared according to method 2,

[0054] 8 h of reflux, Sephadex LH-20, elution with methylene chloride, liquid, yield 92%;elemental analysis: exp. (calc. for C₁₉H₄₀SnO₅.½H₂0): C: 47.7 (47.94); H: 8.8 (8.68); ¹H NMR: 4.09, s, H(2); 3.6-3.8, m, H(4), H(5) & H(7); 3.5-3.6, m, H(8); 3.36, s, H(10);˜2, HOH, 1.5-1.7, m, H(β); 1.2-1.4, m, H(α) & H(γ); 0.89, t (³J(¹H-¹H)=7), H(δ); ¹³C NMR: 175.1, C(I); 72.0, C(8); 70.6, 70.5 & 70.5, C(4), C(5) & C(7); 69.0, C(2); 58.9, C(10); 27.8, C(β) ²J(^(117/119)Sn—¹³C)=20; 27.0, C(γ) ³J(^(117/119)Sn—¹³C)=63/66; 16.6, C(α) ¹J(^(117/119)Sn—¹³C)=349/355; 13.6, C(δ); ¹¹⁷Sn NMR: 120.7; electrospray MS: M+K⁺(m/z=507), 18%; M+Na⁺, 51%; Mössbauer: QS: 3.84; IS: 1.47; γ₁: 1.07; Γ₂: 1.02.

[0055] Compound 14: di-n-butyltin bis (3,6,9-trioxadecanoate), prepared according to method 3,

[0056] 12 h of reflux, liquid, yield 95%; elemental analysis: exp. (calc. for C₂₂H₄₄SnO₁₀ ): C: 44.8 (44.99); H: 7.8 (7.56); ¹H NMR: 4.15, s, H(2); 3.6-3.8, m, H(4), H(5) & H(7); 3.5-3.6, m, H(8); 3.35, s, H(10); 0.6-0.8, m, H(β) & H(α); 1.35, tq (³J(¹H-¹H)=7, ³J(¹H-¹H)=7), H(γ); 0.88, t (³J(¹H-¹H)=7), H(δ); ¹³C NMR: 175.8, C(1); 71.8, C(8); 71.1, 70.6 & 70.4, C(4), C(5) & C(7); 68.7, C(2); 59.0, C(10); 26.6, C(β), ²J(^(117/119)Sn—¹³C)=38; 26.3, C(γ), ³J(^(117/119)Sn—¹³C)=99; 25.6, C(α), ¹J(^(117/119)Sn—¹³C)=540/567; 13.5, C(δ); ¹¹⁷Sn NMR: −124.1; electrospray

[0057] MS: M+K⁺(m/z=627), 12%; M+Na⁺, 22%; Mössbauer: QS: 3.77; IS: 1.42; Γ₁: 1.36; Γ₂: 1.18.

[0058] Compound 15: bis[di-n-butyl(3,6,9-trioxadecanoato)tin]oxide, prepared according to method 3,

[0059] 12 h of reflux, Sephadex LH-20, elution with methylene chloride, liquid, elemental analysis: exp. (calc. for C₆₀H₁₂₄Sn4O₂₂.2 H₂0): C: 42.2 (42.18); H: 7.4 (7.56); yield 80%; ¹H NMR: 3.96, s, H(2); 3.6-3.7, m, H(4), H(5) & H(7); 3.5-3.6, m, H(8); 3.34, s, H(10);=2, HOH; 1.57, tt (³J(¹H-¹H)=7, ³J(¹H-¹H)=7), H(β); 1.4-1.5, m, H(α); 1.27, tq (³J(¹-¹H)=7, ³J(¹H-¹H)=7), H(γ); 0.8-0.9, m, H(δ); ¹³C NMR: 175.1, C(1); 72.0, C(8); 70.60, 70.55 & 70.4, C(4), C(5) & C(7); 69.9, C(2); 59.0, C(10); 27.6 & 27.3, C(β); 26.9 & 26.7, C(γ); 29.1 & 25.8, C(α); 13.6, C(δ); ¹¹⁷Sn NMR: −204.9 & −217.6; electrospray MS: M/2+Na⁺ (m/z=861), 10%; M/2+Bu₂SnOH⁺, 33%; Mössbauer: QS: 3.49; IS: 1.32; Γ₁: 0.90; Γ₂: 0.90.

[0060] Stability in Water of Organotin Polyoxaalkanenecarboxylates

[0061] The stability in the presence of water of four compounds, 6, 8, 9 and 12, was determined. Solutions in CD₃CD₂OD exhibit a single resonance in ¹¹7Sn NMR (at 36.5, −210.7, 27.9 and −212.0 ppm, respectively) that is regularly slightly shifted after the addition of increasing amounts of D₂O.

[0062] Antitumour activity of compounds 1 to 15

[0063] The ID₅₀ inhibition doses in ng/ml of the tested compounds are given in the table as well as those for some known reference compounds. IG- MCF-7 EVSA-T WiDr ROV M19 A498 H226 1 15 12 13 30 16 43 37 2 35 6 11 30 70 97 100 3 155 128 781 260 219 282 281 4 36 46 239 82 68 126 73 5 <3 <3 <3 <3 <3 <3 <3 6 <3 <3 <3 <3 <3 <3 <3 7 273 237 332 321 286 49 854 8 13 12 34 37 31 32 33 9 32 40 82 84 90 153 61 10 60 62 379 128 115 134 161 11 <3 <3 6 <3 <3 <3 5 12 9 9 19 33 24 21 25 13 36 25 40 89 78 93 56 14 86 66 495 178 167 145 280 15 <3 <3 3 <3 <3 <3 <3 cisplatin 699 422 967 169 558 2253 3269 doxorubicin 10 8 11 60 16 90 199 etoposide 2594 317 150 580 505 1314 3934 5-fluoro-uracil 750 475 225 297 442 143 340 methotrexate 18 5 <3 7 23 37 2287

[0064] Inhibition doses ID₅₀ in vitro (in ng/ml) against some tumoural cell lines of human origin, two mammary cancers, (MCF-7, EVSA-T), a colon carcinoma (WiDr), an ovarian cancer (IGROV), a melanoma (M19 MEL), a renal cancer (A 498) and a non small cell lung cancer (H226) of organotin derivatives of carboxybenzocrown and di- or trioxaalkanecarboxylic acids, and of some known reference compounds. 

1. Tin polyoxaalkanecarboxylates having the formula [(R¹ _(p)R² _(q)Sn)_(r)O_(s)]_(t) wherein R¹ represents C₁-C₆ alkyl, branched or straight, substituted or not by one or more hydroxyl groups or halogen atoms, or a phenyl group, substituted or not by one or more hydroxyl groups or halogen atoms, R² is a carboxylic residue selected from:

and p, q, r, s and t have the following meanings: p=3, q=1, r=1, s'0 and t=1; p=2, q=2, r=1, s'0 and t=1; p=2, q=1, r=2, s'1 and t=2.
 2. Anti-tumour compositions, containing as an active ingredient one or more tin polyoxaalkanecarboxylates of the formula R¹ ₃SnR²  (1);R¹ ₂SnR² ₂  (2); or{[R¹ ₂R²Sn]₂O}₂  (3), wherein R¹ and R² have the meanings as defined in claim 1 , and a pharmaceutically acceptable carrier.
 3. A composition according to claim 2 , containing a compound having the formula (1), (2) or (3) as defined in the claims 1 and 2, wherein R¹ represents a phenylgroup or a n-butylgroup. 